G790del mutation in DSC2 alone is insufficient to develop the pathogenesis of ARVC in a mouse model

Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease that causes heart failure and/or sudden cardiac death. Several desmosomal genes (DSC2, PKG, PKP2, DSP, and RyR2) are thought to be the causative gene involved in ARVC. Out of them, DSC2 mutations account for 2% of ARVC genetic abnormalities. This study aimed to clarify the effect of G790del mutation in DSC2 on the arrhythmogenic mechanism and cardiac function in a mouse model. Result Neither the heterozygous +/G790del nor homozygous G790del/G790del mice showed structural and functional defects in the right ventricle (RV) or lethal arrhythmia. The homozygous G790del/G790del 6-month-old mice slightly showed left ventricular (LV) dysfunction. Cell shortening decreased with prolongation of intracellular Ca2+ transient in cardiomyocytes isolated from the homozygous G790del/G790del mice, and spontaneous Ca2+ transients were frequently observed in response to isoproterenol. Conclusions G790del mutation in DSC2 was not relevant to the pathogenesis of ARVC, but showed a slight contractile dysfunction and Ca2+ dysregulation in the LV.
Highlights • We successfully established the DSC2 KI mice of G790del. • Both heterozygous +/G790del and homozygous G790del/G790del mice showed no signs of ARVC. • Homozygous G790del/G790del mice revealed a slight LV dysfunction with aberrant Ca2+ release. • The G790del mutation in DSC2 alone is insufficient to develop ARVC in a mouse model..